Pulmonary hypertension is associated with significant morbidity and mortality, yet therapeutic options remain limited because agents which lower pulmonary vascular resistance (PVR) also lower systemic vascular resistance (SVR) (1). Nitric oxide (NO) gas has recently been shown to selectively lower PVR in pulmonary hypertension (2,3), but concerns remain involving its potential chromosomal effects (4), formation of toxic products from reaction with oxygen (4,5), logistic difficulties associated with delivery of a gas, and its short biological half-life, necessitating constant administration for continued effect (3,6).
Initial observations dealing with the use of cAMP and cGMP compounds go back to models of heart transplantation, where it was demonstrated that these systems were dysfunctional in the blood vessels of a transplanted heart. Supplementation of either the cGMP or the cAMP pathways could enhance the function of blood vessels within the graft, promoting successful transplantation. Stimulators of cAMP pathway used in these experiments included Sp-cAMPs, 8-Br-cAMP, db-cAMP, and phosphodiesterase inhibitors (indolidan, rolipram), all of which helped graft preservation. An antagonist of this pathway (RpcAMPS) blocked the beneficial effects of 8-Br-cAMP.
Nitric oxide is formed by cells lining blood vessels from the amino acid L-arginine, and leads to the formation of cGMP in the nearby cells. In the transplantation model, compounds which give off NO (nitroglycerin, nitroprusside), the NO precursor L-arginine, or 8-Br-cGMP (which acts like native cGMP but is capable of passing through cell membranes and therefore getting into cells) similarly benefitted heart preservation.
Both pathways (cAMP and cGMP) seemed to be dysfunctional in the setting of transplantation because of their roles in maintaining proper blood vessel function. Beneficial effects included improving blood flow, reducing damaging white blood cell infiltrations into blood vessels, preventing blood vessel leakiness, and preventing blood clot formation. The basis for these effects have been described in numerous basic science papers elsewhere, in which the roles of these compounds on these functions had been studied. Experiments performed in the context of lung transplantation indicated that these same beneficial effects were found in the blood vessels of the lungs.